Primary infection with varicella-zoster virus (VZV) causes chickenpox, and reactivation of the virus from latency results in zoster. The purpose of this project is to study the molecular basis for the pathogenesis and latency of VZV. We developed a new model to study VZV latency using the cotton rat. Inoculation of these animals with the Oka vaccine strain of VZV resulted in a latent infection in the nervous system of 50 to 70% of the animals. Viral DNA and RNA can be detected in ganglia from the animals at least one month after inoculation. The pattern of latent infection in the animals resembles that seen in humans naturally infected with the virus. We have tested two VZV mutants which have deletions in individual viral genes in this assay and have determined that these two "knock-out" viruses are still able to establish a latent infection in the nervous system with expression of viral RNA. We have identified the product of a new VZV gene (ORF2) and have shown that it encodes a protein that localizes to the membranes of infected cells. The VZV protein is phosphorylated by a cellular protein kinase. Deletion of the ORF2 gene from the virus does not impair the growth of the virus in cell culture and does not reduce the frequency of latent virus infection. We identified the product of another new VZV gene (ORF17) and found that its product induces RNA cleavage. Deletion of the ORF17 gene from the virus resulted in a mutant that grew similar to parental virus at 33oC, but was markedly impaired for growth at 37oC in cell culture. The mutant virus was not impaired for development of latent infection in animals.